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Frontal Cortical Areas Differ in Response to Stress

10 August 2006. Understanding how stress alters the brain may hold one key to unlocking the puzzle of genetic and environmental interplay in schizophrenia. In this regard, a new study from Conor Liston, Bruce McEwen, and colleagues at Rockefeller University and Mt. Sinai School of Medicine in New York should be of some interest to schizophrenia researchers. Writing in the July 26 issue of the Journal of Neuroscience, they report that subjecting rats to repeated stress causes dendritic loss in the medial prefrontal cortex, but dendritic growth in the orbitofrontal cortex. These distinct morphologic changes were accompanied by distinctly different effects on facets of executive function subserved by these two areas.

Executive function is of particular interest to researchers in schizophrenia because many patients are impaired on tests of cognitive flexibility—they often learn tasks as readily as control subjects, but then have trouble shifting strategies when the rules change. With evidence pointing to traumatic stress as a possible risk factor in schizophrenia (see SRF related news story), this new study provides a possible link between stress-induced brain alterations and some of the cognitive deficits characteristic of schizophrenia.

Previously, McEwen’s group had shown that repeated stress, provided by restraining rats in a wire mesh restrainer for 6 hours daily over 3 weeks, caused retraction and debranching of dendrites and synapse loss in the medial prefrontal cortex (mPFC) (Radley et al., 2006). In the new study, Liston and colleagues confirm this finding for neurons in the anterior cingulate region (ACg) of the mPFC. But a different area of the frontal cortex showed the opposite result: In the orbital frontal cortex (OFC), stress increased dendritic material and branching by 43 and 36 percent, respectively, as assessed by morphometric analysis of apical dendrites after ionophoric cell loading of Lucifer yellow dye. This is the first report of a stress-related increase in arborization of any region in the frontal cortex, the researchers write.

To look for functional consequences of these contrasting changes, the researchers tested the stressed rats for their ability to pay attention to varying environmental cues in order to locate a food reward. The procedure tests several different forms of executive function, including reversal learning (e.g., an odor that predicted reward no longer does so, and vice versa) and extradimensional attentional set-shifting (features of a stimulus that previously had no predictive value, e.g., texture, now are needed to find reward). Specifically, the rats had to find a sweet treat placed in one of two bowls cued with different odors (for example, cloves vs. nutmeg), or different digging material (e.g., plastic vs. Styrofoam beads).

In simple discrimination tests, the stressed rats learned the cue and performed just as well as control rats. Similarly, when the cues were reversed so that the wrong answer became the correct one (reversal learning, which is known to depend on OFC function), the stressed rats learned just as quickly as controls. The stressed rats were not so mentally agile, however, when the relevant cue switched from odor to texture, or vice versa. The stressed animals had a harder time than control rats learning to shift attention to the tactile cue and ignore the scent cue. Dealing with this type of extradimensional set-shift depends upon the mPFC, and morphologic measurements on individual rats strengthened the link between dendritic loss in this region and learning impairments. Animals with the largest stress-related morphologic changes showed the greatest impairments in attentional shifting, while animals with smaller changes performed like controls.

“Collectively, our results indicate that chronic stress induces contrasting morphologic effects in the lateral OFC and ACg, which in turn predict the severity of stress-related impairments in attention shifting,” the authors write. “This study provides the first direct evidence that dendritic remodeling in the prefrontal cortex may underlie the functional deficits in attentional control that are symptomatic of stress-related mental illness.”

An obvious, and open, question is how stress can have different effects on cells in neighboring cortical areas. In this regard, there is a precedent: pyramidal cells in hippocampus respond to stress with dendritic loss, whereas pyramidal cells of the basolateral amygdala show dendritic growth under the same conditions (see, e.g., Vyas et al., 2002 ). As the authors mention, the intra- and extracellular milieus can differ markedly in different brain regions, as well as patterns of innervation from monoaminergic neurons.—Pat McCaffrey.

Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, Morrison JH, McEwen BS. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006 Jul 26;26(30):7870-4. Abstract

Comments on News and Primary Papers
Comment by:  Patricia Estani
Submitted 31 August 2006
Posted 31 August 2006
  I recommend the Primary Papers
Comments on Related News

Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  Margaret Almeida
Submitted 28 June 2006
Posted 30 June 2006
  I recommend the Primary Papers

This article supported absolutely what our research clinic is anecdotally experiencing. On more than several occasions we have conducted a Structured Clinical Interview for DSM-IV Axis I disorders (SCID) to find a diagnosis of schizophrenia or schizoaffective disorder. However, in contrast, the clinical chart is describing psychotic symptoms, but the clinical diagnosis is post-traumatic stress disorder alone or perhaps along with borderline personality disorder with depression. All of these cases involved younger clients (18-25 years old), either just beginning mental health services or certainly without a long history of mental health care to reflect on. They also had histories (according to primary care providers) of severe childhood abuse and trauma.

View all comments by Margaret Almeida

Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  Craig Morgan
Submitted 30 July 2006
Posted 31 July 2006
  I recommend the Primary Papers

This is a fascinating study investigating the relationship between psychological trauma and the development of psychotic symptoms using data from the Early Developmental Stages of Psychopathology (EDSP) study conducted in Munich, Germany.

There are a number of interesting findings: 1) Self-reported trauma (any) was associated with experiencing one (OR 1.40; 95 percent CI 1.09, 1.78), two (OR 1.88; 95 percent CI 1.35-2.62) and three or more (OR 2.60; 95 percent CI 1.66-4.09) psychotic symptoms during the follow-up period. While these odds ratios increase linearly with number of psychotic symptoms, when potential confounders, such as urbanicity and psychosis proneness, were controlled for, only the association with three or more psychotic symptoms remained significant (Adj. OR 1.89, 95 percent CI 1.16-3.08); 2) Most specific categories of trauma showed positive associations with psychotic symptoms, particularly at the level of three or more, though only physical threat, natural catastrophe and terrible event to other reached statistical significance (though this may be largely an issue of statistical power); and 3) There was evidence that the association between trauma and psychotic symptoms varied by psychosis proneness. That is, the association between trauma and psychosis was strongest in those with pre-existing vulnerability to psychosis.

There has been recent controversy, at least in the U.K., about the role of trauma in the etiology of psychosis, largely as a consequence of a review paper published by John Read and colleagues which concluded that child abuse is a cause of schizophrenia (Read et al., 2005). Does the study by Spauwen et al. provide support for this conclusion? The findings allow interpretation both ways.

On the one hand, there is a robust association between any traumatic event and subsequent development of three or more psychotic symptoms. There are also indications that this may be a dose-response relationship. Further, this study has a number of methodological advantages over much of what has gone before. The prospective design overcomes many of the concerns regarding potential recall bias and direction of causation, as does the inclusion of a measure of psychosis proneness. The sample was large, and the analyses sophisticated.

On the other hand, it could be countered, the observed association between any trauma and psychotic symptoms was modest (Adj. OR 1.89) and much smaller than that found in other studies (e.g., Janssen et al. (2004) reported an adjusted odds ratio of 7.3 over a 2-year period). The evidence for a dose-response relationship was weak, and when confounders were adjusted for, only the association with the most severe level of psychotic symptoms remained significant. Furthermore, and issues of statistical power notwithstanding, it is important to note that only a small number of specific types of trauma were significantly associated with risk of developing psychotic symptoms, and these did not include sexual abuse. And there remains the ongoing issue of the relationship, if any, between psychotic-like symptoms reported in general population samples and the clinical syndromes of psychosis, particularly schizophrenia.

So, there are reasons to retain a healthy skepticism, particularly in relation to claims that child abuse causes schizophrenia. But equally, the emerging evidence suggests it would be wrong to reject a possible role for psychological trauma out of hand. Studies are becoming more methodologically robust, and that by Spauwen et al. is an example of this. There is, however, clearly a need for much more research. Until this is available, we should remain open-minded.


Janssen I, Krabbendam L, Bak M, Hanssen M, Vollebergh W, de Graaf R, van Os J. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand. 2004 Jan;109(1):38-45. Abstract

Read J, van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand. 2005 Nov;112(5):330-50. Review. Abstract

View all comments by Craig Morgan

Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  Ezra Susser, SRF Advisor
Submitted 9 August 2006
Posted 9 August 2006

I agree with most of the comments already posted by others on the very interesting paper by Spauwen et al on psychological trauma and psychotic symptoms. I'd like to raise just one additional point. This pertains to the specificity for psychotic symptoms. It appears that the study found no relation of these psychological traumas to depression or bipolar disorder, but it isn't clear whether there was any relation to depressive symptoms. It's worth considering this point in the interpretation of the results, because psychological traumas have been related to a number of other conditions in previous studies.

View all comments by Ezra Susser

Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  Maurits Van den NoortPeggy Bosch
Submitted 10 August 2006
Posted 10 August 2006
  I recommend the Primary Papers

We read the paper by Spauwen et al. (2006) with great interest. Their findings suggest a specific relationship between psychological trauma and psychosis. Previous studies already showed that psychological trauma is clearly associated with depression and other symptoms of post-traumatic stress disorder, but the link between childhood trauma and psychosis was controversial. The current finding is very interesting and based on a study with a large data set and a good methodology. However, more research on this topic needs to be done. This research should measure the type of trauma in greater detail since this could give a better understanding of the exact link between trauma and psychosis. Moreover, the focus of future research should be more on the underlying neurological mechanisms by which childhood trauma increases the risk of psychosis. For instance, it would be interesting to conduct neuroimaging studies (Ni Bhriain et al., 2005), that focus on dopamine abnormalities (McGowan et al., 2004) in patients with traumatic experiences early in life.


McGowan S, Lawrence AD, Sales T, Quested D, Grasby P. Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study. Arch Gen Psychiatry. 2004 Feb;61:134-142. Abstract

Ni Bhriain S, Clare AW, Lawlor BA. Neuroimaging: a new training issue in psychiatry? Psychiat Bull. 2005 May;29:189-192.

Spauwen J, Krabbendam L, Lieb R, Wittchen HU, van Os J. Impact of psychological trauma on the development of psychotic symptoms: relationship with psychosis proneness. Br J Psychiatry. 2006 Jun;188:527-33. Abstract

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Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  James ScottJohn McGrath (SRF Advisor)
Submitted 10 August 2006
Posted 10 August 2006
  I recommend the Primary Papers

Spauwen and colleagues add further weight to research linking traumatic experiences and psychotic symptoms (Spauwen et al., 2006). There are now a number of studies showing an association between trauma and psychotic symptoms (Bebbington et al., 2004; Janssen et al., 2004; Sareen et al., 2005; Shevlin et al., 2006; Whitfield et al., 2005). There are also a number of large community-representative studies showing that psychotic symptoms are highly prevalent in community populations (Eaton et al., 1991; Scott et al., 2006; van Os et al., 2000).

Read and colleagues have argued that child abuse may be an etiological factor for schizophrenia in some individuals (Read et al., 2001; Read et al., 2005). In a clinical study of adolescent inpatients who hallucinated, we found using a structured questionnaire and structured clinical interview (K-SADS) that the hallucinations of schizophrenia and those of post-traumatic stress disorder (PTSD) were very similar in form and content (Scott et al., 2006, in press). Thus, clinicians and researchers need to remain mindful of the overlap of psychotic symptoms in these disorders.

A possible explanation for the above is that psychotic symptoms are non-specific experiences. Perhaps they represent a final common pathway to a range of stressors including unemployment, social isolation, migration, substance use and trauma. From a different perspective in relation to trauma, psychotic symptoms may be part of a dissociative process (van der Kolk et al., 1996), and the positive psychotic symptoms in PTSD are phenomenologically difficult to distinguish from those of schizophrenia.

The association between trauma and psychotic symptoms is a fascinating one requiring further objective, open-minded research.


Bebbington PE, Bhugra D, Brugha T, Singleton N, Farrell M, Jenkins R, Lewis G, Meltzer H. Psychosis, victimisation and childhood disadvantage: evidence from the second British National Survey of Psychiatric Morbidity. Br J Psychiatry. 2004 Sep;185:220-6. Abstract

Eaton WW, Romanoski A, Anthony JC, Nestadt G. Screening for psychosis in the general population with a self-report interview. J Nerv Ment Dis. 1991 Nov;179(11):689-93. Abstract

Janssen I, Krabbendam L, Bak M, Hanssen M, Vollebergh W, de Graaf R, van Os J. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand. 2004 Jan;109(1):38-45. Abstract

Read J, Perry BD, Moskowitz A, Connolly J. The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model. Psychiatry. 2001 Winter;64(4):319-45. Review. Abstract

Read J, van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand. 2005 Nov;112(5):330-50. Review. Abstract

Sareen J, Cox BJ, Goodwin RD, J G Asmundson G. Co-occurrence of posttraumatic stress disorder with positive psychotic symptoms in a nationally representative sample. J Trauma Stress. 2005 Aug;18(4):313-22. Abstract

Scott J, Chant D, Andrews G, McGrath J. Psychotic-like experiences in the general community: the correlates of CIDI psychosis screen items in an Australian sample. Psychol Med. 2006 Feb;36(2):231-8. Epub 2005 Nov 23. Abstract

Scott J, Nurcombe B, Sheridan J, et al. (2006) Hallucinations in Adolescents with Post-traumatic Stress Disorder and Psychotic Disorder. Australasian Psychiatry, In press.

Shevlin M, Dorahy M, Adamson G. Childhood traumas and hallucinations: An analysis of the National Comorbidity Survey. J Psychiatr Res. 2006 Apr 24; [Epub ahead of print] Abstract

Spauwen J, Krabbendam L, Lieb R, Wittchen HU, van Os J. Impact of psychological trauma on the development of psychotic symptoms: relationship with psychosis proneness. Br J Psychiatry. 2006 Jun;188:527-33. Abstract

van der Kolk BA, Pelcovitz D, Roth S, Mandel FS, McFarlane A, Herman JL. Dissociation, somatization, and affect dysregulation: the complexity of adaptation of trauma. Am J Psychiatry. 1996 Jul;153(7 Suppl):83-93. Review. Abstract

van Os J, Hanssen M, Bijl RV, Ravelli A. Strauss (1969) revisited: a psychosis continuum in the general population? Schizophr Res. 2000 Sep 29;45(1-2):11-20. Abstract

Whitfield CL, Dube SR, Felitti VJ, Anda RF. Adverse childhood experiences and hallucinations. Child Abuse Negl. 2005 Jul;29(7):797-810. Abstract

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Related News: Trauma Link to Psychosis Is Strengthened

Comment by:  Ella Matthews
Submitted 24 August 2006
Posted 27 August 2006

Spauwen and colleagues find that exposure to psychological trauma may increase the risk of psychotic symptoms in people vulnerable to psychoses. The experiences of war, natural disasters and child abuse cannot be good for anyone. Am I wrong to think that these add up to much more than psychological trauma or that such events would also tend to bring on and exacerbate the symptoms of myriad other conditions such as those relating to the heart, lungs and other bodily organs?

View all comments by Ella Matthews